Substituted 4,4&#39;-diaminodiphenyl sulfones and process of making same



Pat'ented Jan. 7, 1947 SUBSTITUTED 4,4 DIAMINODIPHENYL SULFONES ANDPROCESS OF MAK-' ING SAME Lucas P. Kyrides, St. Louis, Mo., .assignor toMonsanto Chemical Company, St. Louis, Mo., a

corporation -.of Delaware No Drawing.

"Original application March 20,

1943, Serial No. 479,915. Divided and this .application October 3, 1945,Serial No. 620,158

S'Claims. 1

This invention relates to certain new derivatives of 4,4-diaminodiphenylsulfone and to the process of producing them. 7

This application is a division of my co-pending application, SerialNumber 479,915, filed March 20 1943.

These new products have been found to possess therapeuticactivity in thetreatment of various diseases.

These new derivatives maybe represented by the-following generalformula:

in which X represents a sulfide, disulfide, thionyl, sulfone or oxygenresidue.

In preparing these new products, the procedure in general is thefollowing:

To a solution (or suspension) of one molecular equivalent of4,4'-diaminodiphenyl sulfone in a suitablevsolvent, such as acetone,methyl alcohol, ethyl alcohol, ethylene glycol or-dioxane, is added twomolecular equivalents of the 'anhydride halide or mono-ester acyl halideof an acid selected from the group consisting of diglycolic acid,thiodiglycolic acid, dithiodiglycolic acid, thionyl diglycolic andsulfondiacetic acids. Th reactio-n mixture is desirably refluxed forseveral hours and the solvent thereupon Jremoved by evaporation underreduced pressure. The residue'and oil are solidified by treatment withwater. The solid material is filtered on and dried. The product may bepurified by dissolution in alcohol, filtration through charcoal,addition of water and agitation until crystallization of the product iseffected. Prepared in this manner, the product may retain some Water ofcrystallization, which "maybe removed if desired by drying theproduct,.for example, in a stream of heated'air 'or'in vacuo-at atemperature below :the 'decomp osition point of the product.

For the preparation of the monoacylaminorderivative, one molecularequivalent of the anhydride, halide or mono-ester acyl halide i employedin placeof two molecularequivalentsh As an alternative to thediacylamino compounds, mixed acylamino compounds may be prepared byfirst reacting one molecularequivalent of one of the anhydrides in thegroup hereinbe ore described With the diaminodiphenyl sul'fone and "thenreacting one "molecular equivalent of an- 2 other of the anhydridesinthe group 'hereinbefore described or any other suitable anhydride, forexample, acetic anhydride. .Also, the order of the substitution .may bereversed, for example, firstreactingace'tic anhydride and then reactingone of the .anhydrides in 'thegroup hereinbefore described.

The 4,4'-'diaminodipheny1 sulfone is desirably obtained by refluxing amixture of parachloronitrobenzene and sodium sulfide in water, reactingthe resulting p-aminothiopheno'late with a molecular equivalent of.parachloronitrobenzene, acylating the resulting 4-nitro-4'-aminodiphenylsulfide with acetic anhydride, oxidizing the sulfide to the sulfone,removing the acetyl residue by acid hydrolysis and reducing the 4-nitro4- aminodiphenyl sulfone to thediamino compound.

A desirable procedure for obtaining the monoacylamino derivatives of the:present invention 'comprisesacylating 4-,nitro-4'-aminodiphenyl su1-fidewith am'olecular equivalent of .theanhydride of -one "of the acidsselected "from the group hereinbefore described, oxidizing the 4-nitro-4-acylaminodiphenyl sulfide to the 'sulfone and subsequently reducingthen'itro re'sidue'to'the amine.

A desirable procedure 'for obtaining the diacylamino derivative of thepresent invention comprises reducing 4 nitro-'4-aminodiphenyl sulfide to4,4-diaminodiphenylsulfide, acylating the sulfide with two molecularequivalents of the anhydride of one of "the acids selected from thegroup hereinbefore described, and subsequently oxidizing the sulfide tothe. sulfone.

Both the free acids 'andthe salts of the compounds ofthepresentinvention may be employed for therapeutic'purposes. Examplesof the alkalimetal-saltsare thesodium and potassium salts ofN-'acetyl-Nwliglycolyllyl-diarnirrodipl'lenyl sulfone. These salts maybeprepared, for example, by dissolving a molecular equivalent of thederivative in an aqueous solution of sodium carbonate containing fromone totwo molecular equivalents of the alkali-metal carbonate andrecovering the salt by evaporationof the water. Examples of thealkaline-earth metal salts are the calcium and magnesium salts. Theammonium salts and substituted ammonium salts may also be employed fortherapeutic purposes, and also the mixed ammonium and'alkali metaloralkaline-earth metal salts. In the therapeuticadministration of thederivatives of this invention, the oral method is desirably employed,although parenteral methods may'be employed. In the case of arenteraladminstrat'ion, the acid "may be dissolved in an aqueous solutioncontaining the salt-forming substance, such as sodium hydroxide, and thesolution thus formed may be employed for the treatment.

The following preparations and examples serve to illustrate the generalprocess. It is to be understood, however, that these examples do notlimit the invention since other methods for pre-' paring the compoundsof this inventionare contemplated. I

PREPARATION N0. 1

4-m'tro-4'-aminodiphenyl sulfide This substance may be preparedaccording to the method described in J. Am. Chem. Soc., 61, 2763 (1939),in which p-chloronitrobenzene is refluxed with sodium sulfide in aqueoussolution, the resulting p-aminothiophenolate is refluxed with amolecular equivalent of p-chloronitrobenzene and the reaction mixturesubsequently steam-distilled to remove unchanged p-chloronitrobenzene.The product is crystallized from the nonvolatile portion andrecrystallized from alcohol.

PREPARATION No. 2

4-nitro-4'-aminodiphenyl suljone N A solution of 18.7 grams of4-nitro-4f-aminodiphenyl sulfide, prepared according to the methoddescribed under Preparation No. 1, in 510 cc.

of glacial acetic acid and 161 cc. of acetic anhy-' dride wasrefluxedfor two hours to effect acetylation of the'aminogroup. 800 cc.of glacial acetic acid was'then added and the temperature was adjustedto 90 C. During three hours, 317 cc. of 30% hydrogen peroxide was addeddropwise. The temperature was maintained at 90 C. for an additional halfhour and the mixture was cooled and diluted with 2500 cc. of water. Thecrude 4-nitro-4eacetylaminodiphenyl sulfone was filtered off and washedwith water. This product was mixed with 360 cc. of concentratedhydrochloric acid, 1080 cc. of water and 300 cc. of ethyl alcohol.hours, the mixture was cooled to 30 C., and neutralized with 50% sodalye. The precipitated material was filtered off, washed with water anddried at 80 C. Upon analysis, the product was found to be4-nitro-4='-aminodiphenyl sulfone.

PREPARATION No. 3

4,4'-diaminodiphenyl sulfide This substance may be prepared according tothe method described in J. Am. Chem. Soc., 61,,

2763 (1939), in which a suspension of 4-nitro-4'- aminodiphenyl sulfideis treated simultaneously with tin turnings and hydrochloric acid toreduce the nitro group to amino. After the reduction, the product wasprecipitated from-the reaction mixture with alkali, filtered therefrom,

After refluxing for about ten 7 refluxed in alcohol and recovered byprecipition with water and filtration. The product may be recrystallizedfrom 50% alcohol.

PREPARATION N0. 4

4,4-dz'aminodiphenyl sulfone This substance was prepared according tothe method described in J. Am. Chem. Soc., 61, 2763 (1939), in which4,4-diaminodipheny1 sulfide and acetic. anhydride were refluxed and theresulting 4,4-diacetylaminodiphenyl sulfide was recovered, oxidized tothe sulfone with potassium dichromate in the presence of sulfuric acidand glacial acetic acid, recovered from the reaction mixture and the twoacetyl radicals hydrolyzed 01f with the aid of hydrochloric acid. The4,4- diaminodiphenyl sulfone is thereupon precipitated by adding sodiumcarbonate and the precipitate is recovered and washed. The product maybe purified by refluxing with aqueous alcohol and the purified productrecovered by adding water to the solution, cooling-with ice andseparating the solid product by filtration. In the acylation step anysuitable anhydride, for example, succinic anhydride or propionicanhydride, or the acyl chloride derivatives of succinic or propionicacids, may be utilized.

PREPARATION No.5

Dzglycolic anhydride CHr-G This substance may be prepared according tothe method described in Annalen, 259, (1890), in which diglycolic acidis refluxed with acetyl chloride, excess acetyl chloride is distilledoff and the residue is dissolved in warm chloroform and crystallizedtherefrom on cooling.

PREPARATION No. 6

Th iodz' glycol ic anhydride v CH:(]/

CH -C o This substance may be prepared according to the method describedin Annalen 273, 68 (1893), in which dry thiodiglycolic acid and acetylchloride are heated, excess acetyl chloride is distilled ofi and theresidue is dissolved in warm chloroform and crystallized therefrom oncooling.

PREPARATION No.7

Dithiodiglycolyl dichloride i c1-o-oHs-som 'io1 Dithiodiglycolic acidmaybe prepared according to the method described in GermanPatent No.194,039, in which sodium chloracetate and sodium disulfide are reactedand'the product is recovered from the reaction mixture. In thepreparation or the acyl dichloride, 21.1 grams of dithiodiglycolic acidand 23 grams of thionyl chloride were refluxed in 50 cc. of ben'z'eneforthree hours. The liquid reaction mixture was decanted from insolublematerial and distilled until the solvent and excess thionyl'chlori'dewere removed. The residue, dithiodiglycolyl dichlo= ride, maybe purifiedby conventional methods.

As an alternative to the dichloride, the mono-' ester 'acyl halide, forexample, monomethyl dithiodiglycolyl chloride, may be prepared and used.The bromides and other halides of dithio diglycolic acid may be used. Inusing the-halides and mono-ester halides in preparing the compounds ofthe present invention, it is necessary, after the amide has been formed,to hydrolyze off the remaining halide residue or monoester residue inorder to obtain the free carboxyl compound.

PREPARATION No. 8

Thzonyldiglycolic anhydride CH2-C/ Thionyldiglycolic acid may beprepared according to the method described in J. Chem. Soc. (London),93, 1834, in which thiodiglycolic acid is treated with an excess ofhydrogen'peroxide and theproduct is recovered from the reaction mixture.The anhydride may be prepared according to the methods described inPreparations Nos. 5 and 6.

PREPARATION N0. 9

which thiodiglycolic acid in aqueous alkaline car.- bonate solution isoxidized with potassium permanganate and the product is recovered fromthe reaction mixture. The anhydride may be prepared according to themethods in Preparations Nos. 5 and 6.

EXAMPLE I N -diglycolyl -4,4 diaminodimhny1 sulfone HO Ill A mixture of24.6 grams of 4-amino-4'-nitrodiphenyl sulfide,75 cc. of acetone and 12grams of diglycolic-anhydride was refluxed for two hours and thereafterallowed to stand for ten hours at C. The reaction product,N-diglycolyl-4- amino-4-nitrodiphenyl sulfide, was crystallized from themixture as a yellow solid and was filtered off, washed with acetone anddried. The

acetone mother: liquor was evaporated. Water I was added to the residualoil and the' mixture was 'stirr'e'd until the oil was solidified.Theseus-gee; terial was filtered, washed with water and dried at C.

A solution of 27.8 grams of this material in 80 cc. of glacial aceticacid was prepared and heated to C. During three hours, 31.? cc; of 30%hydrogen peroxide was added dropwise to the solution. The temperaturewas maintained at 90 C. for an additional half hour. Thereafter themixture was cooled and dilutedwitn cc. of water. The precipitatedproductwas filtered off, washed. with water and dried at 80 C. The'prodnot ofthis reaction was N-diglycolyl-4 nitro-4'- aminodiphenyl suli'one. I I yAs an' alternative preparation of N-diglycolylll-nitro4-aminodiphenyl"sulfone, a mixtureof 27.8 grams of 4nitro-4'-aminodiphenyl sulfone,750g; of acetoneiand 12.0 grams of diglycolic an: hydride was refluxedfor twohuors and cooled to 25 C. Upon standing, a yellow solidcrystallized out. The productwas filtered off, washed with acetoneand-dried; weight 32 grams. The acetonefiltrat was evaporated,the'residual oil was treated with 100 cc. of water and the mixture wasstirred until the product solidified. The crystals were filtered off,washed with water-and dried at 80 C. The total yield was 39.4 grams(100%) A mixture of 39.4 grams of N-diglycolyl-4-nitro-Y-aminodiphenylsulfone with35f7 grams of granulated tin in'{250-ccr of alcohol wastreated with 250 'cc: of '10%"hy'drochloric'acid. The mix turewasstirred'for 'four hours at 40-45 C., filtered, and the tin' wasremoved from the filtrate by treatment with hydrogen sulfide. Excess'hydrogen sulfide was dissipated by means of a stream of air or byplacing the solution under vacuum. The solution was alkalinized withsodium bicarbonate, evaporated to dryness under reduced pressure and theresidue was recrystallized. The product wasN-'diglycolyl-4,4='-diaminodiphenyl sulfone. Y

The nitro compound also can-be reduced catalytically withhydrogen, usinga" hydrogenation catalyst;

EXAMPLE II Nahiodigzycdzy'l-rn' didmmodiphenyz sulfone A mixture of 27.8grains of 4- amino-4'-nitro-' diphenyl sulfo-ne, '75 cc. of acetone and14 grams of thiodiglycolic anhydride was refluxed for two hours. Atthis' time, 100 ccjof "water was added and the acetone was evaporatedfrom the mix ture. The solid material wasfiltered off, washed with waterand dried at 80 C. The product of this reaction was Nthiodiglycolyl-4-amino-4- nitrodiphenyl sulfone. A mixture of 41.0 gramsof this product with 35.7 grams of granulated tin in 250 cc. of alcoholwas stirred with250 cc. of 10% hydrochloric acid at 40 45 C. for fourhours. Solids were removed by filtration. and the filtrate was freedfrom tin bytreatment with hydrogen sulfide. Excess hydrogen sulfide wasdissipated by means of ast'ream of-air or by placing the solutionundervacuum. The solution'wa's alkalinized with sodium bicarbonate,evaporated to dryness under reduced pressure and the residue waspurified by recrystallization.

Thenitro compound: also maybe-reduced with 1 hydrogen using a"hydrogenationcatalyst and '7 some suitable solvent, such as an alcohol,dioxane, etc.

EXAMPLE III N-dzthz'odiglycoZyZ-4,4'-diaminodiphenyl sulfone Thisproduct may be prepared according to the method of Example II, usingmonomethyl dithiodiglycolyl chloride in place of thiodiglycolicanhydride, with corresponding changes in the stoichiometricalproportions. The monomethyl residue of the derivative as thus preparedmay be hydrolyzed off by conventional methods, for example, by refluxingthe material in acetone solution with caustic soda. 1

EXAMPLE IV N thionyldiglyco lyl- 4,4 -diamz'nodiphenyl sulfone H o O1I-( JCHZQ-CH:C 0 0H 0: s 40 This product may be prepared according tothe method of Example II, using thionyldiglycolic anhydride in place ofthiodiglycolic anhydride, with corresponding changes in thestoichiometrical proportions.

. EXAMPLE V This compound may be prepared according to the method ofExample I, replacing diglycolic anhydride with sulfondiacetic anhydride.

It is further a feature of this invention that sulfondiacetic anhydridemay be replaced with thiodiglycolic anhydride and the sulfide radicalsof the thiodiglycolyl and aminodiphenyl sulfide residues oxidizedsimultaneously with an excess of hydrogen peroxide to the correspondingsulfones. For example, the diglycolic anhydride of Example I may bereplaced with 14 grams of thiodiglycolic anhydride and the quantity of30% hydrogen peroxide increased to 63.4 00., or twice that required forthe oxidation of one sulfide residue to the corresponding sulfoneresidue.

EXAMPLE VI N thiodigZycoZyZ-N -acetyZ-4,4' -dz'aminodip henyl sulfone llilr-o oms om-coon 8 The product was l T--thiodiglycolyl-N'-ac'etyl-4,4'diaminodiphenyl sulfone.

As an alternative procedure, a molecular equivalent ofN-acetyl-4A-diaminodipheny1 sulfone, prepared according to the methoddescribed in J. Am. Chem. Soc, 61, 2763 (1939), or the method describedin United States Patent No. 2,260,626, issued October 28, 1941 toKleiderer and Van Arendonk, may be reacted with a molecular equivalentof thiodiglycolic anhydride, using the method of the present example, toproduce the product, N acetyl N-thiodiglycolyl-4,4-diaminodiphenylsulfone, which is identical with the product described hereinbefore inthe present example.

Other mixed N-acy1-4/l-diaminodiphenyl sulfone compounds embodying theacyl residues derived from the anhydrides described herein may also beprepared by the methods described in the aforedescribed examples. Amongthese acyl derivatives are the following:

N diglycolyl-N -acetyl N -thiodiglycolyl-N-acetyl N -dithiodiglycolyl-N-acetyl N -thionyldiglyc olyl-N -acetyl N-sulfondiacetyl-N -acetyl Inplace of the anhydrides described hereinbefore, the acyl halides or themono-ester acyl halides of the acids may be employed. In this event,after condensation of the acyl dihalide or the mono-ester acyl halidewith an amino group, the hydrolysis of the residual halide or mono-esterresidue is made necessary in order to'expose the free carboxyl radicalof the acid residue.

As a further alternative, the diaminodiphenyl sulfone or4-nitro-4'-aminodiphenyl sulfone may be condensed With the aciddirectly, forming first an amine salt and subsequently dehydrating theamine salt with the aid of heat and, if desired, a dehydration catalystto accelerate the reaction. The dehydration reaction may be conducted atreduced pressure.

The derivatives of the present invention may be recovered as thehydrates. For example, N ,N-dithiodiglycolyl-4,4-diaminodiphenyl sulfonemay be recovered as the dihydrate andN,N'-di-diglycolyllfl'-diaminodiphenyl sulfone as the trihydrate. Thiswater of hydration may be removed by heating the respective compounds ina stream .of heated air or in vacuo below the temperature at whichdecomposition begins.

I claim:

1. A substituted 4,4-diaminodiphenyl sulfone which is represented by theformula:

represents a residue selected from the group consisting of diglycolyl,thiodiglycolyl, dithiodiglycolyl, thionyldiglycolyl and sulfondiacetylres-

